Exploring the molecular determinants of substrate-selective inhibition of cyclooxygenase-2 by lumiracoxib.

Authors

Windsor MA Matthew A , Valk PL Pieter L , Xu S Shu , Banerjee S Surajit , Marnett LJ Lawrence J .
Bioorganic & medicinal chemistry letters. 2013 11 1; 23(21).
5860-4

PMID: 24060487

Abstract

Lumiracoxib is a substrate-selective inhibitor of endocannabinoid oxygenation by cyclooxygenase-2 (COX-2). We assayed a series of lumiracoxib derivatives to identify the structural determinants of substrate-selective inhibition. The hydrogen-bonding potential of the substituents at the ortho positions of the aniline ring dictated the potency and substrate selectivity of the inhibitors. The presence of a 5′-methyl group on the phenylacetic acid ring increased the potency of molecules with a single ortho substituent. Des-fluorolumiracoxib (2) was the most potent and selective inhibitor of endocannabinoid oxygenation. The positioning of critical substituents in the binding site was identified from a 2.35Å crystal structure of lumiracoxib bound to COX-2.